There have been known that immune systems, especially T cells, play an important role in the elimination of tumors by organisms. In fact, infiltration of lymphocytes has been found in human tumor foci, the lymphocytes showing cytotoxic activity against tumor cells (Arch. Surg., 126:200, 1990). Cytotoxic T cell (CTL) which recognizes autologous tumor cell has been relatively easily isolated from melanomas (Immunol. Today, 8:385, 1987, J. Immunol., 138:989, 1987, Int. J. Cancer, 52:52, 1992, and the like). In addition, the significance of T cells in the tumor elimination has been also suggested from the clinical results of a treatment of melanomas by CTL transfer (J. Natl. Cancer. Inst., 86:1159, 1994).
Although it has been unknown for a long period of time as to the molecule to which CTL attacking autologous tumor cell is targeted, the molecule has gradually been elucidated by the recent progress in immunology and molecular biology. In other words, there has been elucidated that CTL attacks autologous tumor cell by recognizing a complex by using a T cell receptor (TCR), the complex being formed between a peptide called “tumor antigen peptide” and thereafter a major histocompatibility complex class I antigen (MHC class I antigen; in the case of human, it is referred to as HLA antigen).
Tumor antigen peptides are generated by intracellularly synthesizing an inherent protein in a tumor, i.e. a tumor antigen protein, and thereafter intracellularly degrading by proteasome. The generated tumor antigen peptide binds to MHC class I antigen (HLA antigen) in the endoplasmic reticulum, thereby forming a complex, and the formed complex is transported to cell surface, to thereby be antigen-presented. The antigen-presented complex is recognized by tumor-specific CTL to thereby exhibit anti-tumor effects through cytotoxic actions and production of lymphokines. As a series of actions have been elucidated as described above, a treatment for enhancing tumor-specific CTL in the body of a tumor patient can be accomplished by utilizing a tumor antigen protein or tumor antigen peptide as a so-called cancer vaccine.
As the tumor antigen protein, a protein named MAGE was firstly identified from human melanoma cell by T. Boon et al. in 1991 (Science, 254:1643, 1991). Thereafter, some tumor antigen proteins have been identified mainly from melanoma cell. As the melanoma antigen, there have been identified melanosome proteins such as a melanocyte tissue-specific protein gp100 (J. Exp. Med., 179:1005, 1994), MART-1 (Proc. Natl. Acad. Sci. USA, 91:3515, 1994), and tyrosinase (J. Exp. Med., 178:489, 1993); MAGE-associated proteins expressed in not only melanoma cells but also various kinds of cancer cells and normal testis cell (J. Exp. Med., 179:921, 1994); β-catenin possessing tumor-specific amino acid mutations (J. Exp. Med., 183:1185, 1996); CDK4 (Science, 269:1281, 1995), and the like. In addition, as tumor antigen proteins other than melanomas, there have been identified oncogene products such as HER2/neu (J. Exp. Med., 181:2109, 1995) and p53 (mutant) (Proc. Natl. Acad. Sci. USA, 93:14704, 1996); tumor markers such as CEA (J. Natl. Cancer. Inst., 87:982, 1995) and PSA (J. Natl. Cancer. Inst., 89:293, 1997); viral proteins such as HPV (J. Immunol., 154:5934, 1995) and EBV (Int. Immunol., 7:653, 1995), and the like. These tumor antigen proteins are detailed in the description of review (Immunol. Today, 18:267, 1997; J. Exp. Med., 183:725, 1996; Curr. Opin. Immunol., 8:628, 1996, and the like).
For the purpose of the application of a tumor antigen protein or tumor antigen peptide to the treatment or diagnosis for a tumor, it is important to identify a tumor antigen which can be applied in a wide range to squamous cell carcinomas (esophageal cancer, lung cancer and the like) of which occurrence is outnumbered in frequency as compared to that of melanomas. Regarding to the above, the present inventors have tried to clone a gene encoding a tumor antigen protein from squamous carcinoma cells derived from esophageal cancer. As a result, the present inventors have succeeded in cloning a gene encoding a novel tumor antigen protein (SART-1) for the first time from tumor cells other than melanomas, and identified from SART-1 some of the tumor antigen peptide portions of which are presented by binding with HLA-A26 or the like (J. Exp. Med., 187:277, 1998; WO 97/46676).
When these tumor antigen peptides are actually applied for a clinical test, it is desirable to use plural kinds of heterologous tumor antigen peptides as well as a single kind of tumor antigen peptide. In other words, not all cancer cells necessarily express commonly the same tumor antigen. Rather, in consideration of the fact that two or more kinds of heterologous tumor antigen peptides are presented on a single cancer cell, it is thought that a treatment using plural heterologous tumor antigen peptides is more effective. In fact, since an effect was insufficient with a peptide derived from a single tumor antigen for melanoma, the development of a cocktail preparation comprising plural peptides has been tried (Int. J. Cancer, 66:162, 1996; Int. J. Cancer, 67:54, 1996). In view of the background as described above, there has been desired identification of a novel tumor antigen peptide which can be widely applied to squamous cell carcinoma or the like occurring at high frequency.
An object of the present invention is to provide a tumor antigen peptide derived from SART-1. Concretely, an object of the present invention is to provide a tumor antigen peptide derived from SART-1 and a derivative thereof possessing functionally equivalent characteristic; and a therapeutic agent, a prophylactic agent, a diagnostic agent or the like for a tumor, each utilizing these tumor antigen peptide and a derivative thereof in vivo or in vitro. The tumor antigen peptide derived from SART-1 of the present invention is a tumor antigen peptide presented by binding with an HLA antigen HLA-A24, the HLA-A24 being owned by about 60% of the Japanese population, so that the tumor antigen peptide can be applied to a large number of patients, and the tumor antigen peptide can be also widely applied to squamous cell carcinoma or the like occurring at high frequency. Therefore, the tumor antigen peptide is expected for utility as an anti-tumor agent. In this connection, squamous cell carcinoma is one of cancers most frequently encountered among human cancers. In particular, it has been known that squamous cell carcinoma in esophageal cancer or lung cancer relatively demonstrates resistivities to the current chemotherapy or radiotherapy. From these viewpoints, the development of the tumor antigen peptide of the present invention has been expected.